High yield method for stereoselective acylation of tertiary alcohols

Abstract

The present invention is directed to methods of forming esters of tertiary alcohols. The methods include reacting a compound containing a tertiary alcohol with an acyl heteroaromatic ion-based compound of the formula: wherein R1 is an aromatic or aliphatic acid residue; Y is O or S; Z is R2 N; X is selected from the group consisting of wherein R2 and R3 are independently selected from the group consisting of H, C1-6 alkyls, C1-6 substituted alkyls, C1-6 heteroalkyls, C3-8, branched alkyls, C3-8 cycloalkyls, C1-6 substituted heteroalkyls, aryls, substituted aryls, except that R2 is not H when X is C1-6 alkyl aralkyls, C1-6 heteroalkyl aralkyls, C3-8, branched alkyl aralkyls and C3-8 cycloalkyl aralkyls; and R2' is the same as R2 except that R2' is not H; in the presence of a lanthanideIII metal-based catalyst and a base. In preferred embodiments, a substantially pure optical isomer of a compound containing a tertiary alcohol is used and the resultant esters are of sufficient purity so that expensive and time consuming recrystallization or purification steps are avoided.

What is claimed is: 
     
       1. A method of forming esters of camptothecin or camptothecin derivatives, comprising: reacting an acyl heteroaromatic ion-based compound of the formula: ##STR15## wherein A is an anion;   R 1  is an aromatic or aliphatic acid residue;   Y is O or S;   Z is CH or N; and   X is selected from the group consisting of ##STR16## where R 2  and R 3  are independently selected from the group consisting of C 1-6  alkyls, C 1-6  substituted alkyls, C 3-8  branched alkyls, C 3-8  cycloalkyls, aryls, substituted aryls, C 1-6  alkyl aralkyls, C 3-8  branched alkyl aralkyls and C 3-8  cycloalkyl aralkyls; with a camptothecin or camptothecin derivative in the presence of a lanthanide III  metal-based catalyst whereby an ester of a camptothecin or camptothecia derivative is formed.     
     
     
       2. The method of claim 1, wherein said acyl heteroaromatic-ion based compound is formed by reacting an acylating agent with a compound of the formula ##STR17## wherein Z is CH or N; and X is selected from the group consisting of ##STR18## where R 2  and R 3  are independently selected from the group consisting of C 1-6  alkyls, C 1-6  substituted alkyls, C 3-8  branched alkyls, C 3-8  cycloalkyls, aryls, substituted aryls, C 1-6  alkyl aralkyls, C 3-8  branched alkyl aralkyls and C 3-8  -cycloalkyl aralkyls.   
     
     
       3. The method of claim 2, wherein said acylating agent is selected from the group consisting of mixed anhydrides, N-hydroxy-succinimide esters, N-hydroxyphthlamide esters, active esters of carboxylic acids and acid halides. 
     
     
       4. The method of claim 1, wherein X is NR 2  R 3  and Z is CH. 
     
     
       5. The method of claim 1, wherein said lanthanide III  metal-based catalyst is selected from the group consisting of lanthanum, cerium, praseodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium and lutetium-based catalysts. 
     
     
       6. The method of claim 1, wherein said lanthanide III  metal-based catalyst is a scandium III  -based catalyst. 
     
     
       7. The method of claim 6, wherein scandium III  -based catalyst is selected from the group consisting of scandium perhaloalkylsulfonates and scandium C 2-12  alkyldifluormethyl sulfonates. 
     
     
       8. The method of claim 7, wherein said scandium III  -based catalyst is selected from the group consisting of scandium triflate (scandium trifluoromethanesulfonate) and scandium triflimide (scandium trifluoromethanesulfonimide). 
     
     
       9. The method of claim 2, wherein said acylating agent is selected from the group consisting of aliphatic and aromatic active esters of carboxylic acids. 
     
     
       10. The method of claim 9, wherein said aliphatic active ester of a carboxylic acid is selected from the group consisting of N-hydroxysuccinimide (NHS), N-hydroxybenzotriazole, N-hydroxyphthalimide, N-hydroxyazabenzotriazole and benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexaflurorphosphate. 
     
     
       11. The method of claim 9, wherein said aliphatic active ester of a carboxylic acid is a blocked amino acid active ester selected from the group consisting of S- and R-forms of alanine, leucine, isoleucine, phenylalanine, tryptophan, methionine and proline. 
     
     
       12. The method of claim 9, wherein said aliphatic active ester of a carboxylic acid is selected from the group consisting of 2-chloropropionic acid, 2- methylbutyric acid and substantially pure optical isomers of aliphatic active esters of carboxylic acid compounds. 
     
     
       13. The method of claim 2, wherein said acylating agent is a mixed anhydride selected from the group consisting of alkyl trifuloromethyl anhydrides, alkyl paranitrophenyl anhydrides. 
     
     
       14. The method of claim 2, wherein said acylating agent is an N-hydroxy-succinimide ester or N-hydroxyphthalimide ester. 
     
     
       15. The method of claim 2, wherein said acylating agent is an acid halide is selected from the group consisting of acid bromides, acid chlorides, acid fluorides and acid iodides. 
     
     
       16. The method of claim 1, wherein the ratio of said acyl heteroaromatic ion-based compound to said camptothecin or camptothecin derivative from about 5:1 to about 1:5. 
     
     
       17. The method of claim 1, wherein said lanthanide III  metal-based catalyst is present in an amount of from about 20 to about 100 mol % based upon said acyl heteroaromatic ion-based compound. 
     
     
       18. The method of claim 17, wherein said lanthanide III  metal-based catalyst is present in an amount of from about 40 to about 70 mol % based upon said acyl heteroaromatic ion-based compound. 
     
     
       19. The method of claim 1, wherein said reacting is carried out at a temperature of from about -20° to about 60° C. 
     
     
       20. A method of forming a substantially diasterioselective ester of a camptothecin or camptothecin derivative, comprising; reacting a camptothecin or camptothecin derivative with a substantially pure optical isomer of an acyl heteroaromatic ion-based compound of the formula: ##STR19## wherein A is an anion; R 1  is an aromatic or aliphatic acid residue;   Y is O or S;   Z is CH or N; and   X is selected from the group consisting of ##STR20## where R 2  and R 3  are independently selected from the group consisting of C 1-6  alkyls, C 1-6  substituted alkyls, C 3-8  branched alkyls, C 3-8  cycloalkyls, aryls, substituted aryls, C 1-6  alkyl aralkyls, C 3-8  branched alkyl aralkyls and C 3-8  cycloalkyl aralkyls;   in the presence of a lanthanide III  metal-based catalyst whereby a substantially diastereoselective ester of a camptothecin or camptothecin derivative is formed.   
     
     
       21. The method of claim 20, wherein said acyl heteroaromatic-ion based compound is formed by reacting an acylating agent with a compound of the formula ##STR21## wherein Z is CH or N; and X is selected from the group consisting of ##STR22## where R 2  and R 3  are independently selected from the group consisting of C 1-6  alkyls, C 1-6  substituted alkyls, C 3-8  branched alkyls, C 3-8  cycloalkyls, aryls, substituted aryls, C 1-6  alkyl aralkyls, C 3-8  branched alkyl aralkyls and C 3-8  cycloalkyl aralkyls.   
     
     
       22. The method of claim 21, wherein said acylating agent is selected from the group consisting of mixed anhydrides, N-hydroxy succinimide esters, N-hydroxyphthlamide esters, active esters of carboxylic acids and acid halides. 
     
     
       23. The method of claim 20, wherein X is NR 2  R 3  and Z is CH. 
     
     
       24. The method of claim 20, wherein said lanthanide III  metal-based catalyst is selected from the group consisting of lanthanum, cerium, praseodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium and lutetium-based catalysts. 
     
     
       25. The method of claim 20, wherein said lanthanide III  metal-based catalyst is a scandium III  -based catalyst. 
     
     
       26. The method of claim 25, wherein scandium III  -based catalyst is selected from the group consisting of scandium perhaloalkylsulfonates and scandium C 2-12  alkyldifluormethyl sulfonates. 
     
     
       27. The method of claim 26, wherein said scandium III  -based catalyst is selected from the group consisting of scandium triflate (scandium trifluoromethanesulfonate) and scandium triflimide (scandium trifluoromethanesulfonimide). 
     
     
       28. The method of claim 21, wherein said acylating agent is selected from the group consisting of aliphatic and aromatic esters of carboxylic acids. 
     
     
       29. The method of claim 28, wherein said aliphatic active ester of a carboxylic acid is selected from the group consisting of N-hydroxysuccinimide (NHS), hydroxybenzotriazole, N-hydroxyphthalimide and N-hydroxyazabenzotriazole and benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexaflurorphosphate. 
     
     
       30. The method of claim 28, wherein said aliphatic active ester of a carboxylic acid is a blocked amino acid active ester selected from the group consisting S- and R-forms of alanine, leucine, isoleucine, phenylalanine, tryptophan, methionine and proline. 
     
     
       31. The method of claim 28, wherein said aliphatic active ester of a carboxylic acid is selected from the group consisting of 2-chloropropionic acid, 2- methylbutyric acid and substantially pure optical isomers of aliphatic active esters of carboxylic acid compounds. 
     
     
       32. The method of claim 21, wherein said acylating agent is a mixed anhydride selected from the group consisting of alkyl trifuloromethyl anhydrides, alkyl paranitrophenyl anhydrides. 
     
     
       33. The method of claim 21, wherein said acylating agent is an N-hydroxy succinimide ester or an N-hydroxyphthalimide ester. 
     
     
       34. The method of claim 21, wherein said acylating agent is an acid halide is selected from the group consisting of acid bromides, acid chlorides, acid fluorides and acid iodides. 
     
     
       35. The method of claim 20, wherein the ratio of said acyl heteroaromatic ion-based compound to said camptothecin or camptothecin derivative is from about 5:1 to about 1:5. 
     
     
       36. The method of claim 20, wherein said lanthanide III  metal-based catalyst is present in an amount of from about 20 to about 100 mol % based upon said acyl heteroaromatic ion-based compound. 
     
     
       37. The method of claim 36, wherein said lanthanide III  metal-based catalyst is present in an amount of from about 40 to about 70 mol % based upon said acyl heteroaromatic ion-based compound.